Compositions with adrenolytic action for use in therapy

ABSTRACT

INFORMATION CONCERNING THE THERAPEUTIC ACTION OF THE CITRATES OF 2-ACETYL-5-ETHOXYDIMETHYLAMINO CARVACROL IS DISCLOSED. EXPERIMENTS SHOW THAT THE PRODUCTS COUNTERACT THE ADVERSE EFFECTS OF ADRENALINE AT THE LEVEL OF THE ALPHA ACCEPTORS. THIS ACTION IS SPECIFIC AND DISTINGUISHES THE PRODUCTS DESCRIBED OVER THE KNOWN SYMPATHOLYTIC AGENTS, THEREBY PROVIDING PHARMACEUTICAL PREPARATIONS WHICH ARE PARTICULARLY EFFECTIVE AND WELL TOLERATED IN THE CASE OF DISORDERS, PARTICULARLY OCCLUSIONS OF THE ARTERIAL SYSTEM.

Jan. 30, 1973 G. DEDIEU ETAL 3,714,359

COMPOSITIONS WITH ADRENOLYTIC ACTION FOR USE IN THERAPY Filed Feb. 6; 1969 FIG] TIIEI 0 INJECTION OF l/4 mg. TIMEI 4 MINUTES INVENTORS GUY DEDIEU CLAUDE DUFOUR 6Z amajwelw ATTORNEYS United States Patent Ofice Patented Jan. 30, 1973 3,714,359 COMPOSITIONS WITH ADRENOLYTIC ACTION FOR USE IN THERAPY Guy Dedieu, 72 Rue du Palais Gallien, 33 Bordeaux, France, and Claude Dufour, 72 Rue Delabordere, 92 Neuilly-sur-Seine, France Continuation-impart of application Ser. No. 751,761, Aug. 12, 1968. This application Feb. 6, 1969, Ser. No. 797,195 Claims priority, application France, Mar. 31, 1967, 101,148; Aug. 8, 1968, 162,424 Int. Cl. A61k 27/00 US. Cl. 424-311 15 Claims ABSTRACT OF THE DISCLOSURE Information concerning the therapeutic action of the citrates of Z-acetyl-S-ethoxydimethylamino carvacrol is disclosed. Experiments show that the products counteract the adverse effects of adrenaline at the level of the alpha acceptors. This action is specific and distinguishes the products described over the known sympatholytic agents, thereby providing pharmaceutical preparations which are particularly effective and well tolerated in the case of disorders, particularly occlusions of the arterial system.

This application is a continuation-in-part of copending application Ser. No. 751,761, filed on Aug. 12, 1968.

This invention relates to the citrates of 2-acetyl-5- ethoxydimethylamino carvacrol, as described in the above-referenced parent application. More particularly, this application describes supplementary data on the pharmaceutical activity of said citrates.

In application Ser. No. 751,761, attention is directed particularly to the adrenaline-counteracting properties of the products described in said application. These properties had been ascertained on the basis of tests carried out on guinea pigs.

Subsequently continued experimentation has made it possible, on the one hand, to supplement the knowledge of this adrenolytic action with the aid of tests conducted on rabbits and, on the other hand, it has also made it possible to arrive at entirely novel conclusions concerning the specific action of the described novel drug, thus opening up the possibility of therapeutic applications which could not have been envisaged heretofore.

One of the objects of the present invention is to provide a novel therapeutic system utilizing citrates of 2- acetyl-S-ethoxydimethylamino carvacrol.

Another object of the present invention is to provide data concerning the pharmaceutical properties of the citrates of 2-acetyl-S-ethoxydimethylamino carvacrol.

A further object of the invention is to provide medicaments which are particularly effective and Well tolerated in the case of disorders in the arterial system.

A still further object of this application is to provide data making evident the fact that the described pharmaceutical preparations counteract the action of adrenaline at the level of the alpha receptors.

These and other objects and advantages of the present invention will become apparent to those skilled in the art from a consideration of the following specification and claims.

In accordance with the present invention, it has been found that citrates of 2-acetyl-5-ethoxydi'methylamino carvacrol i.e., the compounds described in application Ser. No. 751, 761, wherein the Z-acetyl-S-ethoxydimethylamino carvacrol moiety is of the formula are vasodilators and peripheral sympatholytic agent which act only on the very small blood vessels.

This finding has been rendered evident particularly on the basis of experiments carried out on cats with the aid of the cranial opening technique of Forbes and Wolff. In the course of these experiments, the modifications of the peripheral cortical vessels after the rapid intravenous injection of the novel carvacrol compounds are determined by means of photography.

In this connection, FIGS. 1 and 2 show exemplary photographs resulting from experiments made in accordance with said cranial opening technique. The photographs reproduced in FIGS. 1 and 2 show the appearance of a certain vasodilating effect of the peripheral cortical vessels, an eifect which is all of the more significant the smaller the diameter of the vessel. For vessels having a natural diameter smaller than LOO 1., this increase is continuous and, after a period of time of from 20 minutes to one hour after the injection, it reaches a value of from to specifically for doses smaller than 1 mg./ kg. FIG. 1 shows the vessels at time zero in one particular experiment, and FIG. 2 shows the appearance of the vessels after the injection of one-fourth mg. of the diacid citrates of 2-acetyl-S-ethoxydi-methylamino carvacrol after four minutes.

The present inventors have found particularly that the products used in the present invention act by blocking the alpha receptors of the sympathetic nervous system, thus producing a slackening or relaxation of the vasoconstrictive tonus. It has also been found that the compositions of application Ser. No. 751,761 are specific and exclusive counteractants of nor-adrenaline on the level of the alpha receptors of the smooth arterial muscles.

On the other hand, the conventional sympatholytic agents do not display the properties peculiar to the products according to the present invention and have a counteracting effect both with respect to the alpha receptors and with respect to the beta receptors. This property produces, after the vasodilatation that immediately follows the administration thereof (but is of short duration) and after a secondary and durable vasoconstriction, disorders of the salivary and gastric secretions as well as orthostatic hypotension.

The products used in the present invention may be employed in any of the customary pharmaceutical forms. Although pomades are particularly suitable for the treatment of lesions and cutaneous alterations or impairments, other pharmaceutically acceptable forms, and particularly tablets, may be successfully utilized in cases where an action of a general character is sought. It should, of course, be clear from the context herein that the active ingredient in such pharmaceutical preparations is the mono-, dior triacid citrate of 2-acetyl-5-ethoxydimethylamino carvacrol, whichever is used. These compounds can also be designated as di-, monoand neutral citrates, respectively, of 2-acetyl-5-ethoxydimethylamino carvacrol. The diacid citrate derivative is particularly preferred.

For the purpose of specifying how the products described in the present application are used, one example is given hereinbelow as illustrative. This example is not to be considered as limiting, and it is to be understood that the conditions and data described can be varied by one skilled in the art as desired.

EXAMPLE Sugar-coated tablets are employed. The tablets comprise 45 mg. of the diacid citrate of Z-acetyI-S-ethoxydimethylamino carvacrol and a quantity of sugar excipient sufficient for a finished tablet of 200 mg. Generally, the posology to be provided comprises between 2 and 4 tablets per day for adults, but may be readily increased, if necessary, in view of the low toxicity of the product.

In order to illustrate the therapeutic effect obtained with the administration of the products according to the invention in human therapy, the following summary lists the experiments conducted on various patients. In the interest of simplification and in order to render possible a better understanding of the results which were obtained, the clinical cases to which the observations pertain have been regrouped into two categories. However, this somewhat arbitrary separation should not be considered as having a limitative character.

A first group of 77 patients comprised principally persons affected by arterial atherosclerotic occlusions, which were simple in 32 cases and associated with diabetes in 45 cases. In all of these cases, an extremely favorable action was noted after administration of 3 tablets per day of the product described in the example. Of particular significance is the fact that patients who additionally suffered from an edema associated with ditsal venous lesions were able to see this symptom disappear completely within several days.

For a second group comprising cases of acute arterial occlusions of the type of embolism or thrombosis, a distinct relief of the patients was found after the product of the invention had been administered to them in a dosage of 2 to 4 compressed tablets per day (45 mg. per tablet), depending on the case, over a period of several Weeks and sometimes several months, following a therapy on the basis of anti-coagulants and cardiotonics. Particularly, a very clear reduction of the pain syndromes was observed.

It can thus be seen from the above description that the therapeutic action of the citrates of Z-acetyI-S-ethoxydimethylamino carvacrol is very significant and beneficial.

In particular, the inventors have been able to show that these products counteract local disorders caused by excesses of adrenaline at the level of the alpha receptors. This action is specific and more particularly distinguishes the products used in the invention over the heretofore known sympatholytic agents, thus allowing the preparation of medicaments which are particularly effective and well tolerated in the case of affections of the arterial system.

The indicated quantities of from 90 to 180 mg. per day of a citrate of 2-acetyl-S-ethoxydimethylamino carvacrol correspond to the administration of 2 to 4 compressed tablets dosed at 45 mg. each. This posology has at all times been found to be sufficient, however, the low toxicity of the preparation makes it possible to administer a larger dose, if necessary or required.

It should be clear from the above dscription that pharmaceutically acceptable forms of the active principle are employed, in accordance with the particular requirements, in a dosage suitable for the disorder being treated. Thus, for example, about 90 to 180 mg. per day of the carvacrol derivative is employed for arterial occlusions, while about 1 to 3 grams per day is employed for disorders caused by excesses of adrenaline. The dosage is administered as convenient, for example, intravenously or orally in tablet form with treatments of the arterial system, and topically as pomades or ointments for adrenaline-counteracting effects in the case of lesions and cutaneous impairments.

The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included herein.

We claim:

1. A process for obtaining vasodilating and sympatholytic effects in blood vessels which comprises orally or intravenously administering an effective amount of a di-, monoor neutral citrate of 2-acetyl-S-ethoxydimethylamino carvacrol to a patient effected with an arterial occlusion.

2. The process of claim 1, wherein the citrate administered is the diacid citrate of Z-acetyl-S-ethoxydimethylamino carvacrol.

3. The process of claim 1, wherein the dosage is approximately to mg. per day of the citrate.

4. The process of claim 1, wherein the dosage is administered to the patient intravenously.

5. The process of claim 1, wherein the dosage is administered to the patient orally in tablet form.

6. The process of claim 1, wherein the patient is affected with an arterial atherosclerotic occlusion.

7. The process of claim 1, wherein the patient is effected with embolismor thrombosis.

8. The process of claim 1, wherein the citrate is administered in the form of a pharmaceutical preparation.

9. A process for obtaining vasodilating and sympatholytic effects in blood vessels which comprises orally administering 90 to 180 mg. per day of a di-, monoor neutral citrate of Z-acetyl-S-ethoxydimethylamino carvacrol to a patient affected with an arterial occlusion.

10. The process of claim 9, wherein the citrate administered is the diacid citrate of 2-acetyl-S-ethoxydimethylamino carvacrol.

11. A process for counteracting the local adverse effects caused by excesses of adrenaline at the level of the alpha receptors which comprises toxically administering an effective sympatholytic amount of a di-, monoor neutral citrate of 2-acetyl-5-ethoxydimethylamino carvacrol to a patient so affected.

12. The process of claim 11, wherein the citrate is administered in the form of a pharmaceutical preparation.

13. The process of claim 10, wherein the dosage employed is about 1 to 3 grams per day of the citrate.

14. The process of claim 11, wherein said local adverse effects comprise lesions and cutaneous impairments.

15. The process of claim 12, wherein the pharmaceutical preparation is an ointment.

References Cited UNITED STATES PATENTS 3,262,946 7/1966 Molfett 260326.5

ALBERT T. MEYERS, Primary Examiner F. E. WADDELL, Assistant Examiner 

